Neuroblastoma remains one of the most deadly cancers in children with an overall survival rate for high-risk disease less than 40% despite intensive multi-modal therapy. A deeper understanding of the genetics and biology driving neuroblastoma tumorigenesis may reveal important genes and/or pathways to be targeted therapeutically and will pave the way for molecular diagnostic testing and personalized medicine. We hypothesize that both common and rare copy number variations (CNVs) also influence the genesis of neuroblastoma and that they mark critical genomic regions where somatic alterations and/or mutations occur in primary tumors. This proposal seeks to identify genes important to initiation and progression of neuroblastoma by achieving the following specific aims 1) Identify common constitutional CNVs associated with neuroblastoma through a CNV-based GWAS of 5,000 neuroblastoma cases and 10,000 healthy children as controls. 2) Identify rare constitutional CNVs affecting genes enriched in relevant functional categories and/or pathways associated with neuroblastoma, also utilizing data generated as part of our GWAS effort. 3) Characterize and determine biological relevance of genes influenced by neuroblastoma-associated CNVs. Here, a two-pronged approach is proposed a) a detailed integrative molecular characterization using matched germline and tumor specimens (germline/tumor whole genome sequencing, DNA copy number, DNA methylation, and mRNA/miRNA expression) of all genes directly influenced by neuroblastoma-associated CNVs. b) confirm biological relevance of NBPF23 and NME7, two genes we have demonstrated to be influenced by neuroblastoma-associated CNVs, using molecular biological techniques applied to both developing sympathetic nervous tissue and a large set of annotated tumor tissues. The discoveries generated from this effort will provide substantial insight into both genetic predisposition as well as malignant progression of this important childhood cancer, and will provide the first functional characterization of genes influenced by CNV in neuroblastoma. Discoveries from this study are likely to have broader implications to cancer biology and cancer predisposition. This proposal lays out a 5-year research plan. The first 2-years include a detailed research and training program that will prepare the PI for transition to the independent phase starting year 3 with the goal of obtaining R01 funding prior to year 5. Her mentors and advisors are leaders in the fields of neuroblastoma research, biostatistics, cancer genetics/genomics, and translational research. She will take advantage of the extensive resources of her environment, both at the Children's Hospital of Philadelphia, and the University of Pennsylvania. PUBLIC HEALTH RELEVANCE: Neuroblastoma is the most common extra-cranial solid tumor of childhood and is often lethal. Understanding the genetic events, such as copy number variation (CNV), that drive neuroblastoma tumorigenesis will have considerable relevance to the health of children with this disease as these events may identify molecular pathways critical to the malignant phenotype and thus exploitable therapeutically. Furthermore and as demonstrated in the past, the genes involved in predisposition to neuroblastoma may provide substantial insight into normal human development and cancer biology in general.